RFS Benefit Sustained at 5 Years for Intismeran Autogene in Melanoma

Intismeran autogene (mRNA-4157 or V940), an investigational individualized neoantigen therapy (INT), in combination with pembrolizumab (Keytruda), provides a durable and significant reduction in the risk of recurrence or death compared with pembrolizumab monotherapy in patients with high-risk resected melanoma, according to results reported from a preplanned 5-year follow-up analysis.¹

Long-Term Efficacy Outcomes

The long-term data from the phase 2b KEYNOTE-942/mRNA-4157-P201 study (NCT03897881) showed an improvement to recurrence-free survival (RFS) with a 49% reduction in risk of recurrence or death (HR, 0.510; 95% CI, 0.294–0.887; 2-sided nominal P =.0075) in patients with completely resected stage III/IV melanoma. This finding maintained the 49% reduction that was reported from planned 3-year follow-up in 2023 (HR, 0.501; 95% CI, 0.288–0.906; 1-sided nominal P =.0095).²

“For many patients with stage III/IV melanoma, there is a significant risk of recurrence following surgery. As such, demonstrating the longer-term potential of intismeran autogene and [pembrolizumab] to reduce the risk of recurrence for certain patients with melanoma is a meaningful milestone,” said Marjorie Green, MD, senior vice president and head of oncology, global clinical development, Merck Research Laboratories, in a news release.¹

These findings build upon earlier 2-year and 3-year data, suggesting that the immune response elicited by the personalized mRNA platform is not only robust but also persistent. For oncologists, this represents a potential shift from standard-of-care immunotherapy toward a precision medicine approach that addresses the unique mutational profile of a patient’s specific tumor.

Trial Design and Mechanism of Action

KEYNOTE-942 is an ongoing randomized, open-label phase 2b trial that enrolled 157 patients. Following complete surgical resection, patients were randomly assigned on a 2:1 basis to receive intismeran autogene at 1 mg every 3 weeks for 9 doses plus pembrolizumab at 200 mg every 3 weeks for up to 18 cycles, or pembrolizumab alone for approximately 1 year. The primary end point was RFS, and secondary end points include distant metastasis-free survival and safety.

Intismeran autogene is a novel individualized synthetic mRNA therapy coding for up to 34 patient-specific neoantigens. These neoantigens are identified through genomic sequencing of the patient's resected tumor and a proprietary algorithm. Once administered, the mRNA is translated endogenously, leading to the presentation of these antigens to the immune system. This priming of T-cells is designed to work synergistically with the checkpoint inhibition of pembrolizumab, which prevents the tumor from evading the newly activated immune response.

Safety and Tolerability

According to the latest report, the safety profile of the combination remains consistent with earlier analyses. No new or unexpected late-onset toxicities were identified during the 5-year follow-up period. The most common adverse events remain those typical of mRNA-based platforms, such as fatigue, injection site pain, and pyrexia, as well as the established profile of anti–PD-1 therapy.

The Expanding INT Pipeline

The success of the INTerpath clinical development program has led to rapid expansion into other solid tumors. In melanoma, the phase 3 clinical trial for adjuvant therapy that will confirm these findings, the phase 3 INTerpath-001 trial (NCT05933577) is fully enrolled; this trial will include an estimated 1089 patients with high-risk stage II to IV disease.³ There are 8 phase 2 and phase 3 trials underway, including 2 phase 3 studies currently enrolling patients in both adjuvant and neoadjuvant settings in non–small cell lung cancer, a phase 2 randomized study in renal cell carcinoma, and phase 2 studies ongoing for both muscle-invasive and non–muscle-invasive bladder cancer.¹

The 5-year results from KEYNOTE-942 provide the longest-term evidence to date for the efficacy of individualized mRNA-based neoantigen therapy in the adjuvant setting. It received a breakthrough designation by the FDA in 2023 based on the earlier findings.⁴ Full results from follow-up analyses of primary and secondary end points will be presented at an upcoming medical meeting.¹

“These [5]-year follow up data are encouraging and we look forward to late-stage data from the INTerpath clinical development program with Moderna, across a range of tumor types where significant unmet needs remain,” added Green.¹

REFERENCES

1. Moderna & Merck announce 5-year data for intismeran autogene in combination with keytruda® (pembrolizumab) demonstrated sustained improvement in the primary endpoint of recurrence-free survival in patients with high-risk stage III/IV melanoma following complete resection. News release. Merck. January 20, 2026. Accessed January 20, 2026. https://tinyurl.com/2wcjv9kx

2. Moderna and Merck announce mRNA-4157 (V940) in combination with Keytruda (pembrolizumab) demonstrated continued improvement in recurrence-free survival and distant metastasis-free survival in patients with high-risk stage III/IV melanoma following complete resection versus Keytruda at three years. News release. Merck. December 14, 2023. Accessed January 20, 2026. https://tinyurl.com/mwj5sny8 

3. A clinical study of intismeran autogene (V940) plus pembrolizumab in people with high-risk melanoma (V940-001). ClinicalTrials.gov. Updated September 24, 2025. Accessed January 20, 2026. https://clinicaltrials.gov/study/NCT05933577

4. Moderna and Merck announce mRNA-4157/V940, an investigational personalized mRNA cancer vaccine, in combination with KEYTRUDA® (pembrolizumab), was granted breakthrough therapy designation by the FDA for adjuvant treatment of patients with high-risk melanoma following complete resection. News release. February 22, 2023. Accessed January 20, 2026. https://bit.ly/3xJZLiS